Chronic Rhinosinusitis (CRS) is the most frequently reported chronic disease in the U.S. The etiology of CRS is not well understood. CRS patients are often difficult to treat effectively; even with aggressive medical and surgical therapies, many patients continue to have persistent or recurrent disease. The long-term goal of this project is to understand the causes and pathophysiologic mechanisms of CRS through both clinical and basic research. The specific objective is to delineate the mechanisms causing chronic antigenic stimulation and eosinophilic inflammation in sinus and nasal cavities of CRS patients. The underlying hypothesis to be tested is that immune cells in CRS patients respond to fungi colonized in nasal and sinus cavities and produce large amounts of IL-5 and other inflammatory cytokines, resulting in persistent eosinophilic inflammation of the upper airways. In Aim 1, the altered immunologic responses of CRS patients to fungal antigens are defined. We will examine whether CRS patients' lymphocytes produce more IL-5 and IFN-gamma compared to normal subjects or atopic controls when exposed to fungal antigen(s). The clinical correlation of eosinophil mediators with sinus inflammation and disease severity in patients will be determined. In Aim 2, we will ask why and how eosinophil degranulation occurs in sinus cavities of patients with CRS. We will test the hypothesis that fungal antigen(s) activate and induce eosinophil degranulation through protease-activated receptors (PARs) expressed on eosinophils. The observations in Aim 1 and Aim 2 will be culminated in Aim 3. We will directly ask whether fungal organisms colonized in nasal and sinus cavities cause or exacerbate the disease in CRS patients. By instillation of an antifungal agent, we will remove the colonized fungi from the nasal/sinus cavities of patients and will examine eosinophilic inflammation and clinical outcomes. We believe these studies will lead to a better understanding of the pathophysiologic mechanisms of CRS, especially the underlying causes of antigenic stimulation of immune cells in patients. Elucidation of the causes and mechanisms of inflammation may help to develop specific and effective therapies for this common, costly, and incapacitating disorder.